Spatial protein redistribution: wandering but not lost

Interorganellar spatial redistribution of proteins represents a critical yet underexplored facet of eukaryotic cell biology. This dynamic aspect of proteostasis allows proteins to acquire novel functions based on their subcellular localization, enabling the cell to adapt to both physiological and pathological challenges. Such spatial reprogramming is especially pronounced under stress conditions, including those associated with cancer, neurodegenerative diseases and viral infection, where widespread remodeling of the proteome facilitates survival and adaptation. Despite increasing appreciation of its biological significance, the molecular mechanisms underlying protein relocalization, as well as the functional outcomes of interorganellar trafficking, remain incompletely understood. This review highlights recent advances in the field, with a particular focus on the redistribution of proteins from the endoplasmic reticulum (ER) to other organelles. We provide a detailed examination of a recently characterized mechanism by which cytosolic and ER-resident chaperones and cochaperones mediate the extraction of proteins from the ER into the cytosol. Furthermore, we explore the fate of these relocalized proteins, the mechanistic underpinnings of their trafficking, and how this process compares with other modes of intracellular protein redistribution. Understanding these pathways offers valuable insights into fundamental cell biology and unveils new avenues for therapeutic intervention.